Although antiretroviral therapy (HAART) has decreased the morbidity and mortality associated with HIV infection, it has not eliminated HIV-related complications, such as opportunistic infections and malignancies. Moreover, new, previously unrecognized complications have been identified in HIV-infected patients receiving HAART, that are a consequence of such therapy or the underlying infection itself. Thus, better understanding of the pathogenesis of these complications, and improvements in their diagnosis and treatment, should lead to improvements in the quality of life of HIV-infected patients. Epstein Barr Virus (EBV)-associated primary central nervous system lymphoma (PCNSL) remains a major problem among AIDS patients. The clinical presentation is often clinically indistinguishable from toxoplasmic encephalitis. The method of choice for establishing the definitive diagnosis is brain biopsy. This procedure can be associated with a significant morbidity and mortality, and therefore less invasive means of diagnosing cerebral mass lesions have been studied. Currently, an accepted standard of care for HIV-infected patients that present with signs and symptoms of focal brain lesions is to empirically treat for toxoplasmic encephalitis. Brain biopsy is often deferred until there is demonstration of lack of clinical response or progression on empiric therapy. As a result, treatment initiation is frequently delayed. During this time it is not unusual for further clinical deterioration to occur before appropriate therapies can be initiated. Frequently, the alternative approaches then become a question of appropriate palliation rather than curative intent therapy. Less invasive diagnostic tests to assist in the diagnosis have been investigated. Based on the finding that essentially 100% of HIV-related PCNSL are EBV-associated, the detection of EBV DNA by PCR amplification in the cerebrospinal fluid (CSF) has demonstrated clinical usefulness in the diagnosis, as has the use of neuroradiologic imaging to detect the malignancy. We thus have undertaken a study to evaluate an algorithm for the workup of HIV infected patients with focal brain lesions so as to expedite the diagnosis and subsequent treatment of PCNSL, using the combination of EBV detection in the CSF and FDG-PET scanning. Up to one hundred twenty HIV-infected patients with a history of at least one focal brain lesion will be screened for enrollment. All patients will be treated empirically for toxoplasmic encephalitis until an alternative diagnosis is confirmed. Those patients with a positive EBV-PCR in the CSF or a positive FDG-PET scan will undergo immediate brain biopsy. All enrolled patients will be treated concurrently with antiretroviral therapy. Patients identified to have PCNSL will be referred to an NCI Treatment of PCNSL Protocol for further treatment.